Developing cells acquire mature fates in part by selective (i.e. qualitatively different) expression of a few cell‐specific genes. However, all cells share the same basic repertoire of molecular and subcellular building blocks. Therefore, cells must also specialize according to quantitative differences in cell‐specific distributions of those common molecular resources. Here we propose the novel hypothesis that evolutionarily‐conserved transcription factors called scaling factors (SFs) regulate quantitative differences among mature cell types. SFs: (1) are induced during late stages of cell maturation; (...) (2) are dedicated to specific subcellular domains; and, thus, (3) allow cells to emphasize specific subcellular features. We identify candidate SFs and discuss one in detail: MIST1 (BHLHA15, vertebrates)/DIMM (CG8667, Drosophila); professional secretory cells use this SF to scale up regulated secretion. Because cells use SFs to develop their mature properties and also to adapt them to ever‐changing environmental conditions, SF aberrations likely contribute to diseases of adult onset. (shrink)

In the mammalian central nervous system (CNS), each neuron receives signals from other neurons through numerous synapses located on its cell body and dendrites. Molecules involved in the postsynaptic signaling pathways need to be targeted to the appropriate subcellular domains at the right time during both synaptogenesis and the maintenance of synaptic functions. The presence of messenger RNAs (mRNAs) in dendrites offers a mechanism for synthesizing the appropriate molecules at the right place in response to local extracellular stimuli. (...) Several dendritic mRNAs have been identified, and the mechanisms controlling their localization are beginning to be understood. In many cell types, controls on mRNA stability play an important role in the regulation of gene expression, but it is unclear to what extent this type of control operates in dendrites. The regulation of protein synthesis and the control of mRNA stability in dendrites could have important implications for neuronal function. BioEssays 20:70–78, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

RNA localization is a powerful strategy used by cells to localize proteins to subcellular domains and to control protein synthesis regionally. In germ cells, RNA targeting has profound implications for development, setting up polarities in genetic information that drive cell fate during embryogenesis. The frog oocyte offers a useful system for studying the mechanism of RNA localization. Here, we discuss critically the process of RNA localization during frog oogenesis. Three major pathways have been identified that are temporally and (...) spatially separated in oogenesis. Each pathway uses a different mechanism to effect RNA localization. In some cases, localization elements within the 3' untranslated region have been identified and have provided unique insights into the localization process. This important field is still in its infancy, however, and much remains to be learned. BioEssays 21:546–557, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

RNA localization is a powerful strategy used by cells to localize proteins to subcellular domains and to control protein synthesis regionally. In germ cells, RNA targeting has profound implications for development, setting up polarities in genetic information that drive cell fate during embryogenesis. The frog oocyte offers a useful system for studying the mechanism of RNA localization. Here, we discuss critically the process of RNA localization during frog oogenesis. Three major pathways have been identified that are temporally and (...) spatially separated in oogenesis. Each pathway uses a different mechanism to effect RNA localization. In some cases, localization elements within the 3' untranslated region have been identified and have provided unique insights into the localization process. This important field is still in its infancy, however, and much remains to be learned. BioEssays 21:546–557, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

In the mammalian central nervous system (CNS), each neuron receives signals from other neurons through numerous synapses located on its cell body and dendrites. Molecules involved in the postsynaptic signaling pathways need to be targeted to the appropriate subcellular domains at the right time during both synaptogenesis and the maintenance of synaptic functions. The presence of messenger RNAs (mRNAs) in dendrites offers a mechanism for synthesizing the appropriate molecules at the right place in response to local extracellular stimuli. (...) Several dendritic mRNAs have been identified, and the mechanisms controlling their localization are beginning to be understood. In many cell types, controls on mRNA stability play an important role in the regulation of gene expression, but it is unclear to what extent this type of control operates in dendrites. The regulation of protein synthesis and the control of mRNA stability in dendrites could have important implications for neuronal function. BioEssays 20:70–78, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

Cell morphogenesis encompasses all processes required to establish a three-dimensional cell shape. Cells acquire the architecture specific to their developmental context by using the spatial information provided by internal or external cues. As a response to these signals, cells become reorganized and establish functionally distinct subcellular domains that ultimately lead to morphological changes. In its simplest form, cell morphogenesis results in the establishment of asymmetry along one axis, a cell polarity. Although cell polarity has been studied intensively in (...) budding yeast and epithelial cells, little is known about more complex modes of cell morphogenesis involving multiple axes. In this review we compare the regulation of cell morphogenesis of different genetically well-characterized cell types in Arabidopsis thaliana. BioEssays 20:20–29, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

Cell morphogenesis encompasses all processes required to establish a three-dimensional cell shape. Cells acquire the architecture specific to their developmental context by using the spatial information provided by internal or external cues. As a response to these signals, cells become reorganized and establish functionally distinct subcellular domains that ultimately lead to morphological changes. In its simplest form, cell morphogenesis results in the establishment of asymmetry along one axis, a cell polarity. Although cell polarity has been studied intensively in (...) budding yeast and epithelial cells, little is known about more complex modes of cell morphogenesis involving multiple axes. In this review we compare the regulation of cell morphogenesis of different genetically well-characterized cell types in Arabidopsis thaliana. BioEssays 20:20–29, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

Membranous organelles allow sub‐compartmentalization of biological processes. However, additional subcellular structures create dynamic reaction spaces without the need for membranes. Such membrane‐less organelles (MLOs) are physiologically relevant and impact development, gene expression regulation, and cellular stress responses. The phenomenon resulting in the formation of MLOs is called liquid–liquid phase separation (LLPS), and is primarily governed by the interactions of multi‐domain proteins or proteins harboring intrinsically disordered regions as well as RNA‐binding domains. Although the presence of RNAs affects the (...) formation and dissolution of MLOs, it remains unclear how the properties of RNAs exactly contribute to these effects. Here, the authors review this emerging field, and explore how particular RNA properties can affect LLPS and the behavior of MLOs. It is suggested that post‐transcriptional RNA modification systems could be contributors for dynamically modulating the assembly and dissolution of MLOs. (shrink)

Poly(ADP‐ribosyl)ation is an immediate DNA‐damage‐dependent post‐translational modification of histones and other nuclear proteins that contributes to the survival of injured proliferating cells. Poly(ADP‐ribose) polymerases (PARPs) now constitute a large family of 18 proteins, encoded by different genes and displaying a conserved catalytic domain in which PARP‐1 (113 kDa), the founding member, and PARP‐2 (62 kDa) are so far the sole enzymes whose catalytic activity has been shown to be immediately stimulated by DNA strand breaks. A large repertoire of sequences encoding (...) novel PARPs now extends considerably the field of poly(ADP‐ribosyl)ation reactions to various aspects of the cell biology including cell proliferation and cell death. Some of these new members interact with each other, share common partners and common subcellular localizations suggesting possible fine tuning in the regulation of this post‐translational modification of proteins. This review summarizes our present knowledge of this emerging superfamily, which might ultimately improve pharmacological strategies to enhance both antitumor efficacy and the treatment of a number of inflammatory and neurodegenerative disorders. A provisional nomenclature is proposed. BioEssays 26:882–893, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The DAP (Death Associated Protein) kinase family is a novel subfamily of pro-apoptotic serine/threonine kinases. All five DAP kinase family members identified to date are ubiquitously expressed in various tissues and are capable of inducing apoptosis. The sequence homology of the five kinases is largely restricted to the N-terminal kinase domain. In contrast, the adjacent C-terminal regions are very diverse and link individual family members to specific signal transduction pathways. There is increasing evidence that DAP kinase family members are involved (...) in both extrinsic and intrinsic pathways of apoptosis and may play a role in tumor progression. This review will focus on structural composition and subcellular localization of DAP kinase family members and on signal transduction pathways leading to their activation. Potential mechanisms of DAP kinase family-mediated apoptosis will be discussed. BioEssays 23:352–358, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Electrical signaling by neurons depends on the precisely ordered distribution of a wide variety of ion channels on the neuronal surface. The mechanisms underlying the targeting of particular classes of ion channels to specific subcellular sites are poorly understood. Recent studies have identified a new class of protein‐protein interaction mediated by PDZ domains, protein binding modules that recognize specific sequences at the C terminus of membrane proteins. The PDZ domains of a family of synaptic cytoskeleton‐associated proteins, typified (...) by PSD‐95, bind to the intracellular C‐terminal tails of NMDA receptors and Shaker‐type K+ channels. This interaction appears to be important in the clustering and localization of these ion channels at synaptic sites. Recognition of specific C‐terminal peptide sequences by different PDZ domain‐containing proteins may be a general mechanism for differential targeting of proteins to a variety of subcellular locations. (shrink)

Ubiquitination is essential in mediating diverse cellular functions including protein degradation and trafficking. Ubiquitin‐protein (E3) ligases determine the substrate specificity of the ubiquitination process. The Nedd4 family of E3 ligases is an evolutionarily conserved family of proteins required for the ubiquitination of a large number of cellular targets. As a result, this family regulates a wide variety of cellular processes including transcription, stability and trafficking of plasma membrane proteins, and the degradation of misfolded proteins. The modular architecture of the proteins, (...) comprising a C2 domain, multiple WW domains and a catalytic domain, enables diverse intermolecular interactions and recruitment to various subcellular locations. The WW domains commonly mediate interaction with substrate proteins; however, an increasing number of Nedd4 targets do not contain obvious WW domain‐interaction motifs suggesting the involvement of accessory proteins. This review discusses recent insights into how accessory and adaptor proteins modulate the activities of Nedd4 family members, including recruitment of novel substrates, alteration of subcellular localisation and effects on ubiquitination. BioEssays 28: 617–628, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Every year, unfavorable environmental factors significantly affect crop productivity and threaten food security. Plants are sessile; they cannot move to escape unfavorable environmental conditions, and therefore, they activate a variety of defense pathways. Among them are processes regulated by stress‐associated proteins (SAPs). SAPs have a specific zinc finger domain (A20) at the N‐terminus and either AN1 or C2H2 at the C‐terminus. SAP proteins are involved in many biological processes and in response to various abiotic or biotic constraints. Most SAPs play (...) a role in conferring transgenic stress resistance and are stress‐inducible. The emerging field of SAPs in abiotic or biotic stress response regulation has attracted the attention of researchers. Although SAPs interact with various proteins to perform their functions, the exact mechanisms of these interactions remain incompletely understood. This review aims to provide a comprehensive understanding of SAPs, covering their diversity, structure, expression, and subcellular localization. SAPs play a pivotal role in enabling crosstalk between abiotic and biotic stress signaling pathways, making them essential for developing stress‐tolerant crops without yield penalties. Collectively, understanding the complex regulation of SAPs in stress responses can contribute to enhancing tolerance against various environmental stresses through several techniques such as transgenesis, classical breeding, or gene editing. (shrink)

Traditional understanding of how psychotropic drugs work emphasize highly specific actions at subcellular levels. This model appears to have implications that seriously conflict with our usual view of human agency and autonomy, raising not just theoretical quandaries but contributing to patient reluctance to utilize these drugs. Furthermore, it discourages both meaningful treatment integration and appreciation of the uniqueness of patients. Through a consideration of antidepressants in particular, this paper argues for a more comprehensive model based on nonlinear dynamics and (...) chaos theory that can be applied across multiple domains. This model yields important suggestions for reconciling perspectives in neuroscience with traditional views of human agency. It also encourages real integration of clinical and research approaches in psychiatry, and further defines the components of respectful treatment of patients. (shrink)

The rel family of proteins can be defined as a group of proteins that share sequence homology over a 300 amino acid region termed the rel domain. The rel family comprises important regulatory proteins from a wide variety of species and includes the Drosophila morphogen dorsal, the mammalian transcription factor NF‐kB, the avian oncogene v‐rel, and the cellular proto‐oncogene c‐rel. Over the last two years it has become apparent that these proteins function as DNA‐binding transcription factors, and that their activity (...) is regulated at the level of subcellular localization. (shrink)

Two experiments examined the restriction of referential domains during unscripted conversation by analyzing the modification and online interpretation of referring expressions. Experiment 1 demonstrated that from the earliest moments of processing, addressees interpreted referring expressions with respect to referential domains constrained by the conversation. Analysis of eye movements during the conversation showed elimination of standard competition effects seen with scripted language. Results from Experiment 2 pinpointed two pragmatic factors responsible for restriction of the referential domains used by (...) speakers to design referential expressions and demonstrated that the same factors predict whether addressees consider local competitors to be potential referents during online interpretation of the same expressions. These experiments demonstrate, for the first time, that online interpretation of referring expressions in conversation is facilitated by referential domains constrained by pragmatic factors that predict when addressees are likely to encounter temporary ambiguity in language processing. (shrink)

Two lines of evidence indicate that there exists a reciprocal inhibitory relationship between opposed brain networks. First, most attention-demanding cognitive tasks activate a stereotypical set of brain areas, known as the task-positive network and simultaneously deactivate a different set of brain regions, commonly referred to as the task negative or defaultmode network. Second, functional connectivity analyses show that these same opposed networks are anti-correlated in the resting state. Wehypothesize that these reciprocally inhibitory effects reflect two incompatible cognitive modes, each of (...) which may be directed towards understanding the external world. Thus, engaging onemode activates one set of regions and suppresses activity in the other.Wetest this hypothesis by identifying two types of problem-solving task which, on the basis of prior work, have been consistently associated with the task positive and task negative regions: tasks requiring social cognition, i.e., reasoning about the mental states of other persons, and tasks requiring physical cognition, i.e., reasoning about the causal/mechanical properties of inanimate objects. Social and mechanical reasoning tasks were presented to neurologically normal participants during fMRI. Each task type was presented using both text and video clips. Regardless of presentation modality, we observed clear evidence of reciprocal suppression: social tasks deactivated regions associated with mechanical reasoning and mechanical tasks deactivated regions associated with social reasoning. These findings are not explained by self-referential processes, task engagement, mental simulation,mental time travel or external vs. internal attention, all factors previously hypothesized to explain default mode network activity. Analyses of resting state data revealed a close match between the regions our tasks identified as reciprocally inhibitory and regions of maximal anti-correlation in the resting state. These results indicate the reciprocal inhibition is not attributable to constraints inherent in the tasks, but is neural in origin. Hence, there is a physiological constraint on our ability to simultaneously engage two distinct cognitive modes. Furtherwork is needed tomore precisely characterize these opposing cognitive domains. (shrink)

In order to maximize human performance, defence forces continue to explore, develop, and apply human performance enhancement (HPE) methods, ranging from pharmaceuticals to (bio)technological enhancement. This raises ethical, legal, and societal concerns and requires organizing a careful reflection and deliberation process, with relevant stakeholders. We discuss a range of ethical, legal, and societal aspects (ELSA), which people involved in the development and deployment of HPE can use for such reflection and deliberation. A realistic military scenario with proposed HPE application can (...) serve as a starting point for such an iterative and participatory process. Stakeholders can discuss this application, modify its features, and design appropriate processes around it – for instance, procedures for informed consent. We propose that organizing aspects into these three categories – ethical, legal, and societal – can help involve appropriate interlocutors at different moments: legal aspects with people in strategy or management roles, from the start of a project; ethical aspects with people in operations and medical roles, during development; and societal aspects with people in communication and personnel roles, during deployment. Notably, we developed and discussed this framework and the three aspects in close collaboration with personnel from the military. (shrink)

The best accuracy arguments for probabilism apply only to credence functions with finite domains, that is, credence functions that assign credence to at most finitely many propositions. This is a significant limitation. It reveals that the support for the accuracy-first program in epistemology is a lot weaker than it seems at first glance, and it means that accuracy arguments cannot yet accomplish everything that their competitors, the pragmatic (Dutch book) arguments, can. In this paper, I investigate the extent to (...) which this limitation can be overcome. Building on the best arguments in finite domains, I present two accuracy arguments for probabilism that are perfectly general—they apply to credence functions with arbitrary domains. I then discuss how the arguments’ premises can be challenged. We will see that it is particularly difficult to characterize admissible accuracy measures in infinite domains. (shrink)

A good account of normative reasons should explain not only what makes practical and epistemic reasons a unified kind of thing, but also why practical and epistemic reasons are substantively differ...

According to Weyl, “‘inexhaustibility’ is essential to the infinite”. However, he distinguishes two kinds of inexhaustible, or merely potential, domains: those that are “extensionally determinate” and those that are not. This article clarifies Weyl's distinction and explains its enduring logical and philosophical significance. The distinction sheds lights on the contemporary debate about potentialism, which in turn affords a deeper understanding of Weyl.

Ever since Darwin people have worried about the sceptical implications of evolution. If our minds are products of evolution like those of other animals, why suppose that the beliefs they produce are true, rather than merely useful? We consider this problem for beliefs in three different domains: religion, morality, and commonsense and scientific claims about matters of empirical fact. We identify replies to evolutionary scepticism that work in some domains but not in others. One reply is that evolution (...) can be expected to design systems that produce true beliefs in some domain. This reply works for commonsense beliefs and can be extended to scientific beliefs. But it does not work for moral or religious beliefs. An alternative reply which has been used defend moral beliefs is that their truth does not consist in their tracking some external state of affairs. Whether or not it is successful in the case of moral beliefs, this reply is less plausible for religious beliefs. So religious beliefs emerge as particularly vulnerable to evolutionary debunking. (shrink)

In a series of cross-cultural investigations of word meaning, Cliff Goddard and Anna Wierzbicka examine key expressions from different domains of the lexicon - concrete, abstract, physical, sensory, emotional, and social. They focus on complex and culturally important words in a range of languages that includes English, Russian, Polish, French, Warlpiri and Malay."--Publishers website.

This book offers an innovative, unified theoretical model for better understanding of the processes underpinning naming and framing and the power of words in shaping our perceived reality.

The aim of this work was to elaborate on the author’s previously published hypothesis of the Soul of Multiverse, a suggested cosmic phenomenon that also appears to imbue the human Soul across its individual and noospheric scales. Without alternatives, the method of analysis continued to rely on the approach of cosmological neuroscience, which integrates scientific facts, religious insights, philosophical suggestions, engineering rules and artistic tools to grasp the complexity of the multidimensional phenomenon of Soul. The result of this examination was (...) the multilayered thought that just as the central medium of human Soul, the hypothesized prefrontal cortical supercircuitry of Self-Ken, seems to comprise domains representing Identity, Conscience, Will and Mission, analogous domains may also function in the noospheric and cosmic Souls. Regarding the human Soul, its four domains appear to be determined by both hereditary genetic and encountered environmental factors to present its host with a Mission enabling his or her mental engine and physical features to integrate into the surrounding society and space-time in the most meaningful and dignified way—if that way is undertaken. Regarding the noospheric Soul, it is made of individual human Souls interacting with the non-living system of interconnected computers to produce functions accessible to humans all over the world through uncontrolled communication across the Internet. Its most probable Mission is to let this global presence acquire its own Identity, develop its own Conscience and refine its own Will, so that their coherent, superior whole can be ready for sensing the cosmic Soul. Regarding the cosmic Soul, the hypothesized Soul of the Multiverse, its Identity appears to express the Laws of Mystery of Endlessness, Coexistence in Diversity, and Truth in Complexity. Further, its Conscience seems to be moved by the Law of Divine—Evil Asymmetry, its Will by the Law of Determination with Uncertainty, and its Mission by the Law of Lives to Transcend. (shrink)

The rate‐limiting step in the uptake and metabolism of Dglucose by insulin target cells is thought to be glucose transport mediated by glucose transporters (primarily the GLUT4 isoform) localized to the plasma membrane. However, subcellular fractionation, photolabelling and immunocytochemical studies have shown that the pool of GLUT4 present in the plasma membrane is only one of many subcellular pools of this protein. GLUT4 has been found in occluded vesicles at the plasma membrane, clathrin‐coated pits and vesicles, early endosomes, (...) and tubulo‐vesicular structures; the latter are analogous to known specialized secretory compartments. Tracking the movement of GLUT4 through these compartments, and defining the mechanism and site of action of insulin in stimulating this subcellular trafficking, are major topics of current investigation. Recent evidence focuses attention on the exocytosis of GLUT4 as the major site of insulin action. Increased exocytosis may be due to decreased retention of glucose transporters in an intracellular pool, or possibly to increased assembly of a vesicle docking and fusion complex. Although details are unknown, the presence in GLUT4 vesicles of a synaptobrevin homologue leads us to propose that a process analogous to that occurring in synaptic vesicle trafficking is involved in the assembly of GLUT4 vesicles into a form suitable for fusion with the plasma membrane. Evidence that the pathways of signalling from the insulin receptor and of GLUT4 vesicle exocytosis may converge at the level of the key signalling enzyme, phosphatidylinositol 3‐kinase, is discussed. (shrink)

Theoretical models and correlational research suggest that anger and disgust play different roles in moral judgment. Anger is theorized to underlie reactions to crimes against persons, such as battery and unfairness, and disgust is theorized to underlie reactions to crimes against nature, such as sexual transgressions and cannibalism. To date, however, it has not been shown that induction of these two emotions has divergent effects. In this experiment we show divergent effects of anger and disgust. We use sounds to elicit (...) anger and disgust, and participants are then asked to consider moral vignettes. As compared to disgust and control condition, anger increases severity of judgments about crimes against persons, and disgust increases severity of judgments about crimes against nature, but not conversely. (shrink)